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Objectives : PD-1 and PD-L1 overexpression in malignant tumors in response to radiotherapy is correlated with a poor prognosis. Human papilloma virus (HPV) infection impacts intrinsic radiosensitivity of head and neck cancers (HNCs). Herein, this study aims to determine PD-1/PD-L1 expression differences in tumors with different HPV statuses and their prognostic value in patients with different radiosensitivity gene signatures to define the characteristics of patients who will benefit from radiotherapy combined with anti-PD-1/PD-L1 therapy. Material and methods : According to the identified gene signature related to radiosensitivity, 517 patients from the TCGA HNSCC cohort were selected and divided into the radioresistant (RR) group and radiosensitive (RS) group using a K-mean clustering algorithm. All data analyses were conducted using SPSS and GraphPad Prism. Results : PD-L1 expression is upregulated in tumor tissue (unpaired t test, P=0.0363; paired t test, P=0.0584) compared with normal tissue. PD-L1 was positively correlated with PD-1 expression (P&lt;0.0001). The HPV/p16-positive group was significantly high PD-1 expression (P&lt;0.0001). PD-L1 expression (P=0.0005) and PD-1 expression (P&lt;0.0001) were significantly increased in the RS group compared with that in the RR group. In the patients who were treated with radiotherapy, the PD-1-high group was associated with better recurrence-free survival (RFS) (HR, 0.4892; 95% CI, 0.2357-1.015; P=0.023). Within the RR group, high PD-L1 expression was associated with reduced overall survival (OS) (HR, 2.196; 95% CI, 1.081-4.46; P=0.0108) compared with low PD-L1 expression. In the RR group, HPV/p16-negative patients with high PD-L1 expression exhibited reduced OS (HPV: HR, 2.334; 95% CI, 0.7828-6.961; P=0.0313; p16: HR,2.486; 95% CI, 0.8559-7.219; P=0.0192) compared with that of patients with low PD-L1 expression. In the PD-L1-high group, RR patients exhibited reduced OS (HR, 0.4858; 95% CI, 0.2136-1.105; P=0.0189) and RFS (HR, 0.4371; 95% CI, 0.1421-1.345; P=0.0231) compared with that of RS patients. Conclusion : Our findings demonstrated that high PD-1/PD-L1 expression was strongly related to radiosensitivity, and high PD-1 expression was significantly associated with HPV/p16-positive HNCs. Patients in the radioresistant group and patients in the HPV/p16-negative group with a radioresistant gene signature could benefit from the combination of radiotherapy and anti-PD-1/PD-L1 therapy.

PD-1 and PD-L1 Expression Predicts Radiosensitivity and Clinical Outcomes in Head and Neck Cancer and is Associated with HPV Infection